Metabolic Reprogramming Is Required for Myofibroblast Contractility and Differentiation

Bernard, Karen; Logsdon, Naomi J.; Ravi, Saranya; Xie, Na; Persons, Benjamin P.; Rangarajan, Sunad; Żmijewski, Jaroslaw W.; Mitra, Kasturi; Liu, Gang; Darley‐Usmar, Victor; Thannickal, Victor J.

doi:10.1074/jbc.m115.646984

Cited by 163 publications

(156 citation statements)

References 68 publications

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“…It is well established that tumor cell-secreted transforming growth factor-beta (TGF-β) drives myofibroblastic differentiation[18,40], and that TGF-β-mediated activation of the mitogen-activated protein kinases (MAPK) pathway contributes to this process[41,42]. Interestingly, TEVs also contain TGF-β[37], but whether TEVs promote ASC myofibroblast differentiation through activating the MAPK signaling cascade remains unclear.…”

Section: Resultsmentioning

confidence: 99%

Breast cancer-derived extracellular vesicles stimulate myofibroblast differentiation and pro-angiogenic behavior of adipose stem cells

et al. 2017

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Adipose-derived stem cells (ASCs) are abundantly present in the mammary microenvironment and can promote breast cancer malignancy by differentiating into myofibroblasts. However, it remains largely unclear which role tumor-derived extracellular vesicles (TEVs) play in this process. Here, we used microfabricated, type I collagen-based 3-D tissue culture platforms to investigate the effect of breast cancer cell-derived TEVs on ASCs myofibroblast differentiation and consequential changes in extracellular matrix remodeling and vascular sprouting. TEVs collected from MDA MB-231 human metastatic breast cancer cells (MDAs) promoted ASC myofibroblast differentiation in both 2-D and 3-D culture as indicated by increased alpha smooth muscle actin (α-SMA) and fibronectin (Fn) levels. Correspondingly, TEV-treated ASCs were more contractile, secreted more vascular endothelial growth factor (VEGF), and promoted angiogenic sprouting of human umbilical vein endothelial cells. These changes were dependent on transforming growth factor beta (TGF-β)-related signaling and tumor cell glutaminase activity as their inhibition decreased TEV-related myofibroblastic differentiation of ASCs and related functional consequences. In summary, our data suggest that TEVs are important signaling factors that contribute to ASC desmoplastic reprogramming in the tumor microenvironment, and suggest that tumor cell glutamine metabolism may be used as a therapeutic target to interfere with this process.

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Section: Resultsmentioning

confidence: 99%

Breast cancer-derived extracellular vesicles stimulate myofibroblast differentiation and pro-angiogenic behavior of adipose stem cells

et al. 2017

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“…They also noted that partially blocking glycolysis by inhibiting 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 is effective in suppressing human lung fibroblast differentiation into myofibroblast [46]. A study by Bernard and colleagues also supports the view that myofibroblast contractility and differentiation are related to metabolic reprogramming, which is associated with the activation of the p38 mitogen-activated protein kinase (MAPK) pathway [47]. Although studies have found myofibroblast differentiation is linked to a dysregulation of cellular metabolism, the exact mechanism is unclear.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide DNA methylation analysis in lung fibroblasts co-cultured with silica-exposed alveolar macrophages

Yao

Zhang

et al. 2017

Respir Res

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BackgroundExposure to crystalline silica is considered to increase the risk of lung fibrosis. The primary effector cell, the myofibroblast, plays an important role in the deposition of extracellular matrix (ECM). DNA methylation change is considered to have a potential effect on myofibroblast differentiation. Therefore, the present study was designed to investigate the genome-wide DNA methylation profiles of lung fibroblasts co-cultured with alveolar macrophages exposed to crystalline silica in vitro.MethodsAM/fibroblast co-culture system was established. CCK8 was used to assess the toxicity of AMs. mRNA and protein expression of collagen I, α-SMA, MAPK9 and TGF-β1 of fibroblasts after AMs exposed to 100 μg /ml SiO2 for 0–, 24–, or 48 h were determined by means of quantitative real-time PCR, immunoblotting and immunohistochemistry. Genomic DNA of fibroblasts was isolated using MeDIP-Seq to sequence. R software, GO, KEGG and Cytoscape were used to analyze the data.ResultsSiO2 exposure increased the expression of collagen I and α-SMA in fibroblasts in co-culture system. Analysis of fibroblast methylome identified extensive methylation changes involved in several signaling pathways, such as the MAPK signaling pathway and metabolic pathways. Several candidates, including Tgfb1 and Mapk9, are hubs who can connect the gene clusters. MAPK9 mRNA expression was significantly higher in fibroblast exposed to SiO2 in co-culture system for 48 h. MAPK9 protein expression was increased at both 24-h and 48-h treatment groups. TGF-β1 mRNA expression of fibroblast has a time-dependent manner, but we didn’t observe the TGF-β1 protein expression.Conclusion Tgfb1 and Mapk9 are helpful to explore the mechanism of myofibroblast differentiation. The genome-wide DNA methylation profiles of fibroblasts in this experimental silicosis model will be useful for future studies on epigenetic gene regulation during myofibroblast differentiation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-017-0576-z) contains supplementary material, which is available to authorized users.

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“…6). Mitochondria elongation resulting from insufficient mitophagy may be associated with metabolic reprogramming of mitochondria, which has been demonstrated to be involved in the mechanisms for TGF-b-induced myofibroblast differentiation (35). Therefore, it is reasonable to postulate that elongated mitochondria are responsible for energy (ATP) production during myofibroblast differentiation and proliferation.…”

Section: Discussionmentioning

confidence: 99%

Involvement of PARK2-Mediated Mitophagy in Idiopathic Pulmonary Fibrosis Pathogenesis

Kobayashi

Araya

Minagawa

et al. 2016

The Journal of Immunology

116

117

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Fibroblastic foci, known to be the leading edge of fibrosis development in idiopathic pulmonary fibrosis (IPF), are composed of fibrogenic myofibroblasts. Autophagy has been implicated in the regulation of myofibroblast differentiation. Insufficient mitophagy, the mitochondria-selective autophagy, results in increased reactive oxygen species, which may modulate cell signaling pathways for myofibroblast differentiation. Therefore, we sought to investigate the regulatory role of mitophagy in myofibroblast differentiation as a part of IPF pathogenesis. Lung fibroblasts were used in in vitro experiments. Immunohistochemical evaluation in IPF lung tissues was performed. PARK2 was examined as a target molecule for mitophagy regulation, and a PARK2 knockout mouse was employed in a bleomycin-induced lung fibrosis model. We demonstrated that PARK2 knockdown-mediated mitophagy inhibition was involved in the mechanism for activation of the platelet-derived growth factor receptor (PDGFR)/PI3K/AKT signaling pathway accompanied by enhanced myofibroblast differentiation and proliferation, which were clearly inhibited by treatment with both antioxidants and AG1296, a PDGFR inhibitor. Mitophagy inhibition–mediated activation of PDGFR signaling was responsible for further autophagy suppression, suggesting the existence of a self-amplifying loop of mitophagy inhibition and PDGFR activation. IPF lung demonstrated reduced PARK2 with concomitantly increased PDGFR phosphorylation. Furthermore, bleomycin-induced lung fibrosis was enhanced in PARK2 knockout mice and subsequently inhibited by AG1296. These findings suggest that insufficient mitophagy-mediated PDGFR/PI3K/AKT activation, which is mainly attributed to reduced PARK2 expression, is a potent underlying mechanism for myofibroblast differentiation and proliferation in fibroblastic foci formation during IPF pathogenesis.

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Metabolic Reprogramming Is Required for Myofibroblast Contractility and Differentiation

Cited by 163 publications

References 68 publications

Breast cancer-derived extracellular vesicles stimulate myofibroblast differentiation and pro-angiogenic behavior of adipose stem cells

Breast cancer-derived extracellular vesicles stimulate myofibroblast differentiation and pro-angiogenic behavior of adipose stem cells

Genome-wide DNA methylation analysis in lung fibroblasts co-cultured with silica-exposed alveolar macrophages

Involvement of PARK2-Mediated Mitophagy in Idiopathic Pulmonary Fibrosis Pathogenesis

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